How do the genomic variants in individuals with sporadic Alzheimer's Disease (SAD) contribute to the development of Alzheimer's Disease (AD)? To begin addressing this question human induced pluripotent stem cell (hIPSC) technology will be used to begin testing the hypothesis that the genomes of individual SAD patients contain genetic variants that generate biochemically detectable phenotypes in human neurons. Human pluripotent stem cells (hIPSC) allow the genomes of human individuals afflicted with SAD to be captured in a pluripotent stem cell line. Such cells can then be differentiated to human neurons or glia in vitro for evaluating whether the captured genome alters neuronal or glial phenotype in a manner similar to that seen in cells carrying FAD mutations or as predicted by mechanistic models of SAD such as the Ass hypothesis. An hIPSC model may also be useful for addressing human specific effects and avoiding some aspects of the well known limitations of animal models such as high copy number in transgenic models and the absence of a human genetic background. Our underlying hypothesis is that the genome of a patient with SAD contains a set of susceptibility variants that may alter neuronal, glial, or other relevant cellular phenotypes in a detectable manner. Broadly speaking, genomic variants in SAD patients could contribute to disease in a variety of ways ranging from effects on inflammatory pathways, glial turnover of Ass or other potentially toxic molecules generated by neurons and other cells, or by effects in neurons on pathways of APP processing, susceptibility to Ass poisoning, tau hyperphosphorylation, oxidative damage, etc. In this R21 exploratory proposal, we propose to take the first step and use hIPSC technology to test the hypothesis that at least some SAD genomes cause APP expression, APP processing, or tau phosphorylation phenotypes in human neurons that carry the genomes of patients who developed SAD. Identification of such genomes would provide the raw material for further studies using high resolution molecular genetic analyses to define how different genomic variants contribute to neuronal phenotypes and might allow new drug targets and pathways to be identified. Possible predictive measures and diagnostics might also be generated. In this pilot project, we will probe these issues by completing two specific aims: 1) We will generate 3 hIPSC lines each from 5 SAD patients and 5 age-matched normal controls (NC). 2) We will generate purified neurons from each hIPSC line and test whether SAD neurons exhibit APP expression, APP processing, or tau phosphorylation changes typical of FAD. PUBLIC HEALTH RELEVANCE: Sporadic Alzheimer's Disease is a major public health problem that develops in as much as 10% of the population older than 65 and 50% of the population older than 85. There are currently no disease altering therapeutic strategies although some agents offer temporary symptomatic relief. We propose to use stem cell technology to discover how genetic variation predisposes to Alzheimer's Disease with the hope that this work will allow new therapeutics and predictive diagnostics to be developed.